Development of Inhibitors Targeting Flavivirus Methyltransferase

黄病毒甲基转移酶抑制剂的开发

基本信息

批准号：
10636605
负责人：
HONGMIN LI
金额：
$ 76.74万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-07 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636605
关键词：
3-Dimensional Adverse effects Animal Model Annual Reports Antiviral Agents Antiviral Therapy Arbovirus Encephalitis Binding Biochemical Biochemistry Biological Assay Cells Cellular Assay Cessation of life Chemicals Child Country Crystallography Dengue Infection Dengue Vaccine Dengue Virus Development Disease Disease Outbreaks Drug Kinetics Effectiveness Enzymes Epidemic Flavivirus Flavivirus Infections Fluorescence Fluorescence Resonance Energy Transfer Genome Human Human Cell Line In Vitro Infection Innate Immune Response Insecta Investigation Japanese encephalitis virus Label Lead Methods Methylation Methyltransferase Microcephaly Modeling Molecular Morbidity - disease rate Newborn Infant Organoids Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Poison Populations at Risk Positioning Attribute Prevention Public Health RNA RNA Caps RNA replication Research Research Personnel Resources Risk Serotyping Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Vaccination Vaccines Viral Viral Physiology Virus Virus Diseases Virus Replication West Nile virus Work Yellow Fever Vaccine Yellow Fever Virus Infection Yellow fever virus ZIKV infection Zika Virus analog anti-viral efficacy candidate validation combat cytotoxicity design drug candidate drug testing genomic RNA high throughput screening human pathogen in vivo inhibitor innovation insight lead candidate lead optimization mortality mouse model nanomolar novel scaffold screening small molecule inhibitor structural biology synergism tool vaccine hesitancy viral genomics virology

项目摘要

Abstract: Flaviviruses are primarily insect-borne, associated with global morbidity and mortality, and found on every inhabited continent. Unfortunately, current therapeutic options for treating diseases associated with these viruses are limited. All flaviviruses encode methyltransferases (MTases)—flaviviral NS5 for both N-7 and 2'-O methylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genome, whereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activities are conserved among the flaviviruses. For this project, our collaborative team will optimize the current lead compounds, perform high throughput screening (HTS) to identify additional lead candidates, chemically optimize the lead candidates, and define structure activity relationships. Optimizing current lead compounds using cutting- edge medicinal chemistry, the team will perform a large scale HTS campaign using innovative fluorescence chemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We will perform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry, structural biology, virology, in vivo pharmacokinetics, and in vivo animal models, which will allow the development of novel, effective, broad-spectrum, and druglike therapeutic agents against both flaviviruses. Preliminary progress has been made in the identification of initial lead inhibitors of these MTases, demonstrating low nanomolar antiviral activity. We will advance these compounds to further develop potent antiviral compounds while conducting large- scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among our investigators will synergize and expedite the progress of this research. Our collaborative objective is to provide first-in-class drug candidates for the treatment or prevention of these viral infections.

抽象的：黄病毒主要是昆虫传播的，与全球发病率和死亡率相关，并且存在于每一种生物体中。不幸的是，目前治疗与这些病毒相关的疾病的治疗选择。所有黄病毒均编码甲基转移酶 (MTase)——N-7 和 2'-O 的黄病毒 NS5。病毒基因组 RNA 的甲基化对于病毒 RNA 基因组的复制至关重要。而2'-O MTase功能是病毒逃避宿主先天免疫反应所必需的。对于这个项目，我们的合作团队将优化当前的领先优势。化合物，进行高通量筛选 (HTS) 以识别其他先导候选物，进行化学优化先导候选物，并使用切削化合物优化当前的先导化合物。边缘药物化学，该团队将利用创新荧光进行大规模高温超导活动我们将使用化学探针来识别黄病毒 RNA 加帽 MTase 的其他小分子抑制剂。使用体外生物化学、结构性方法对作用模型和抗病毒功效进行深入研究生物学、病毒学、体内药代动力学和体内动物模型，这将有助于开发新的、针对这两种黄病毒的有效、广谱、类药治疗剂已取得初步进展。已鉴定出这些 MTase 的初始先导抑制剂，证明了低纳摩尔抗病毒作用我们将推进这些化合物，以进一步开发有效的抗病毒化合物，同时进行大规模的研究。我们同时进行规模筛选，以发现更多的结构支架。研究人员将协同并加快这项研究的进展，我们的合作目标是提供。用于治疗或预防这些病毒感染的一流候选药物。